EP2607353B1 - "Nouveau procédé de synthèse de l'ivabradine et de ses sels d'addition à un acide pharmaceutiquement acceptable" - Google Patents

"Nouveau procédé de synthèse de l'ivabradine et de ses sels d'addition à un acide pharmaceutiquement acceptable" Download PDF

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Publication number
EP2607353B1
EP2607353B1 EP12191902.1A EP12191902A EP2607353B1 EP 2607353 B1 EP2607353 B1 EP 2607353B1 EP 12191902 A EP12191902 A EP 12191902A EP 2607353 B1 EP2607353 B1 EP 2607353B1
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EP
European Patent Office
Prior art keywords
group
optionally substituted
heteroaromatic
aromatic
process according
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Application number
EP12191902.1A
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German (de)
English (en)
French (fr)
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EP2607353A1 (fr
Inventor
Jean-Luc Renaud
Nicolas Pannetier
Jean-Pierre Lecouve
Lucile Vaysse-Ludot
Solenne Moulin
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Laboratoires Servier SAS
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Laboratoires Servier SAS
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Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Priority to SI201230089T priority Critical patent/SI2607353T1/sl
Priority to PL12191902T priority patent/PL2607353T3/pl
Publication of EP2607353A1 publication Critical patent/EP2607353A1/fr
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Priority to CY20141100832T priority patent/CY1115682T1/el
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J35/00—Catalysts, in general, characterised by their form or physical properties
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

Definitions

  • the present invention relates to a process for synthesizing ivabradine of formula (I): or 3- ⁇ 3 - [ ⁇ [(7S) -3,4-dimethoxybicyclo [4.2.0] octa-1,3,5-trien-7-yl] methyl ⁇ (methyl) amino] propyl ⁇ -7,8 -dimethoxy-1,3,4,5-tetrahydro- 2H- 3-benzazepin-2-one, of its addition salts with a pharmaceutically acceptable acid and their hydrates.
  • Ivabradine as well as its addition salts with a pharmaceutically acceptable acid, and more particularly its hydrochloride, have very interesting pharmacological and therapeutic properties, especially bradycardic properties, which render these compounds useful in the treatment or prevention of different clinical situations of myocardial ischemia such as angina pectoris, myocardial infarction and associated rhythm disorders, as well as in various pathologies including rhythm disorders, especially supraventricular, and in heart failure.
  • Reductive amination is a preferred route for preparing amines. Since it does not require isolation of the intermediate imine formed, this coupling reaction between an aldehyde and an amine in the presence of a reducing agent is largely used for the synthesis of molecules of interest in the pharmaceutical or agrochemical field as well as in materials science.
  • patent EP 1 589 005 describes the synthesis of ivabradine hydrochloride from the compound of formula (II): which is subjected to a catalytic hydrogenation reaction in the presence of hydrogen and a palladium catalyst to yield the compound of formula (III): which, without being isolated, is reacted in the presence of hydrogen and a palladium catalyst with the compound of formula (IV): to lead to ivabradine of formula (I), in the form of hydrochloride.
  • the present application describes a route of synthesis of ivabradine that eliminates the use of a precious metal.
  • L 1 , L 2 and L 3 independently represent a carbonyl, nitrile, isonitrile, heteroaromatic, phosphine, phosphite, phosphonite, phosphoramidite, phosphinite, phospholane, phospholene, aliphatic amine, aromatic amine, heteroaromatic amine, amine group carrying an electron-withdrawing group , aliphatic ether, aromatic ether, heteroaromatic ether, sulfone, sulfoxide, sulfoximine, or N- heterocyclic carbene having one of the following two formulas: wherein Y and Z independently represent a sulfur or oxygen atom, or an NR 8 group, wherein R 8 represents an optionally substituted alkyl group, an optionally substituted aromatic or heteroaromatic group, K represents a carbon or nitrogen atom, R 9 , R 10 independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aromatic or heteroaromatic group, a
  • iron Unlike precious metal derivatives, those of iron are generally non-toxic and iron salts are abundantly present in nature. These are metallic species that are not harmful to the environment.
  • the present invention provides the use of iron complexes which are furthermore easy to handle.
  • Iron complexes are known to catalyze reductive amination reactions in the presence of silyl hydrides ( Enthaler S. ChemCatChem 2010, 2, 1411-1415 ) but only two examples in the literature describe a reductive amination based on a catalytic hydrogenation ( Bhanage BM et al Tet. Lett. 2008, 49, 965-969 ; Beller M. et al. Chem Asian J. 2011, 6, 2240-2245 ).
  • NTf is the abbreviation for trifluoromethanesulfonamide.
  • Table 1 ⁇ / b> Results of reductive amination reactions catalyzed by iron (II) salts Iron (II) salt (mol%) Quantity (mol%) of EDTANa 2 Temperature (° C) observations 1 FeSO 4 .7H 2 O (2) 10 150 0% ivabradine - degradation 2 FeSO 4 .7H 2 O (2) 10 85 0% ivabradine 3 FeCl 2 .4 H 2 O (5) 10 85 0% ivabradine 4 FeBr 2 .4H 2 O (5) 10 85 0% ivabradine 5 Fe (BF 4 ) 2 .6H 2 O (5) 10 85 0% ivabradine 6 Fe (NTf 2 ) 2 .6H 2 O (5) 10 85 0% ivabradine 0% ivabradine
  • the Beller publication describes the reductive amination of various aldehydes by aniline derivatives in the presence of Fe 3 (CO) 12 in toluene under 50 bar of hydrogen at 65 ° C.
  • the reactions were carried out in a 20 mL autoclave in the presence of 4 mL of degassed solvent.
  • An electron-withdrawing group is a group that attracts electrons more than would a hydrogen atom that would occupy the same position in the molecule.
  • electron-withdrawing groups mention may be made, without limitation, of the following groups: ester, acid, nitrile, aldehyde, ketone, amide, nitro, sulphone, sulphoxide, sulphoximine, sulphonamide or phosphoric diester.
  • the catalyst of formula (VIII) used in the reductive amination reaction of the compound of formula (V) with the compound of formula (VI) is preferably chosen from the following catalysts:
  • the catalyst of formula (XIII) used in the reductive amination reaction of the compound of formula (V) with the compound of formula (VI) is preferably chosen from the following catalysts:
  • the iron-based catalyst used in the reductive amination reaction of the compound of formula (V) with the compound of formula (VI) has the following formula:
  • the iron-based catalyst used in the reductive amination reaction of the compound of formula (V) with the compound of formula (VI) has the following formula:
  • the amount of catalyst involved in the reductive amination reaction of the compound of formula (V) with the compound of formula (VI) is between 1% and 10 mol% relative to the aldehyde.
  • the amount of trimethylamine N- oxide used in the reducing animation reaction of the compound of formula (V) with the compound of formula (VI) is between 0 and 3 equivalents relative to the catalyst, more preferably between 0.5 and 1.5 equivalents relative to the catalyst.
  • the pressure of dihydrogen during the reductive amination reaction of the compound of formula (V) with the compound of formula (VI) is preferably between 1 and 20 bar, more preferably between 1 and 10 bar, still more preferably between 1 and 5 bars.
  • solvents that can be used to carry out the reductive amination reaction of the compound of formula (V) with the compound of formula (VI)
  • the solvent preferentially used to carry out the reductive amination reaction of the compound of formula (V) with the compound of formula (VI) is ethanol.
  • the temperature of the reductive amination reaction between the compound of formula (V) and the compound of formula (VI) is preferably between 25 and 100 ° C., more preferably between 50 and 100 ° C., still more preferably between 80 and 100 ° C. 100 ° C.
  • the catalysts used in the process of the invention may be prepared according to the methods described in the following publications: Synlett 1992, pp1002-1004 , Synlett 1993, pp924-926 and Advanced Synthesis and Catalysis 2012, 354 (4), pp597-601 .
  • a mixture of 5 mol% of iron complex and 5 mol% of trimethylamine N- oxide in 1 ml of ethanol is prepared for 30 minutes in a Schlenk tube under an argon atmosphere and then introduced into the autoclave.
  • the autoclave is then pressurized with hydrogen (5 bar) and the reaction medium is stirred for 16 hours at 85 ° C. and the autoclave is then brought back to ambient temperature and decompressed.
  • the reaction medium is filtered on neutral alumina deactivated (3% water) using ethyl acetate as solvent.
  • the crude product is purified on silica gel (eluent: pentane / ethyl acetate (95/5) with 0.5% triethylamine) to obtain the expected product.
  • reaction medium is filtered on neutral alumina deactivated (3% water) using ethyl acetate as solvent.
  • the crude product is purified on silica gel (eluent: pentane / ethyl acetate (95/5) with 0.5% triethylamine) to obtain the expected product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Materials Engineering (AREA)
  • Inorganic Chemistry (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Catalysts (AREA)
  • Saccharide Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP12191902.1A 2011-12-20 2012-11-09 "Nouveau procédé de synthèse de l'ivabradine et de ses sels d'addition à un acide pharmaceutiquement acceptable" Active EP2607353B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
SI201230089T SI2607353T1 (sl) 2011-12-20 2012-11-09 Nov postopek sintetize ivabradina in njegovih dodatnih soli s farmacevtsko sprejemljivo kislino
PL12191902T PL2607353T3 (pl) 2011-12-20 2012-11-09 Nowy sposób syntezy iwabradyny i jej soli addycyjnych z kwasem farmaceutycznie dopuszczalnym
CY20141100832T CY1115682T1 (el) 2011-12-20 2014-10-14 Νεα μεθοδος συνθεσης ιβαβραδινης και των αλατων προσθηκης της με ενα φαρμακευτικως αποδεκτο οξυ

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR1103933A FR2984319B1 (fr) 2011-12-20 2011-12-20 Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable

Publications (2)

Publication Number Publication Date
EP2607353A1 EP2607353A1 (fr) 2013-06-26
EP2607353B1 true EP2607353B1 (fr) 2014-08-27

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Country Status (35)

Country Link
US (1) US8513410B2 (uk)
EP (1) EP2607353B1 (uk)
JP (1) JP5670406B2 (uk)
KR (1) KR101470879B1 (uk)
CN (1) CN103172566B (uk)
AR (1) AR088678A1 (uk)
AU (1) AU2012244188B2 (uk)
BR (1) BR102012028614A2 (uk)
CA (1) CA2795741C (uk)
CL (1) CL2012003136A1 (uk)
CY (1) CY1115682T1 (uk)
DK (1) DK2607353T3 (uk)
EA (1) EA026510B1 (uk)
ES (1) ES2525032T3 (uk)
FR (1) FR2984319B1 (uk)
GE (1) GEP20156350B (uk)
HK (1) HK1186733A1 (uk)
HR (1) HRP20141023T1 (uk)
JO (1) JO3031B1 (uk)
MA (1) MA34276B1 (uk)
MD (1) MD4336C1 (uk)
MX (1) MX2012012938A (uk)
MY (1) MY170662A (uk)
PE (1) PE20131097A1 (uk)
PL (1) PL2607353T3 (uk)
PT (1) PT2607353E (uk)
RS (1) RS53541B1 (uk)
SA (1) SA112330994B1 (uk)
SG (1) SG191471A1 (uk)
SI (1) SI2607353T1 (uk)
TW (1) TWI440627B (uk)
UA (1) UA111329C2 (uk)
UY (1) UY34423A (uk)
WO (1) WO2013093220A1 (uk)
ZA (1) ZA201208160B (uk)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2988720B1 (fr) * 2012-03-27 2014-03-14 Servier Lab Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
CN105669554A (zh) * 2016-02-22 2016-06-15 徐建立 一种盐酸伊伐布雷定杂质及其制备方法和应用
FR3071833B1 (fr) * 2017-09-29 2020-01-03 Universite Paris-Sud Nouveau procede de synthese d'amines tertiaires dissymetriques

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2681862B1 (fr) * 1991-09-27 1993-11-12 Adir Cie Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent.
US6225487B1 (en) * 1998-04-17 2001-05-01 Symyx Technologies, Inc. Ancillary ligands and metal complexes, catalysts and compositions using same and methods of testing
US6521793B1 (en) * 1998-10-08 2003-02-18 Symyx Technologies, Inc. Catalyst ligands, catalytic metal complexes and processes using same
FR2868777B1 (fr) * 2004-04-13 2006-05-26 Servier Lab Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable
EP1595888A1 (en) * 2004-05-11 2005-11-16 Degussa AG Cycloolefin phosphine ligands and their use in catalysis
ES2381771T3 (es) * 2006-11-30 2012-05-31 Cadila Healthcare Limited Procedimiento para la preparación de hidrocloruro de ivabradina
US7857994B2 (en) 2007-05-30 2010-12-28 GE Lighting Solutions, LLC Green emitting phosphors and blends thereof
EP2471780B1 (en) * 2007-05-30 2014-11-26 Ind-Swift Laboratories Limited Crystalline Ivabradine Oxalate Salts and Polymorphs Thereof
FR2920773B1 (fr) 2007-09-11 2009-10-23 Servier Lab Derives de 1,2,4,5-tetrahydro-3h-benzazepines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2933975B1 (fr) * 2008-07-17 2011-02-18 Servier Lab Nouveau procede de preparation de benzocyclobutenes fonctionnalises,et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable.
FR2935381B1 (fr) * 2008-08-29 2010-12-17 Servier Lab Nouveau procede de resolution des enantiomerees du (3,4-dimethoxy-bicyclo°4.2.0!octa-1,3,5-trien-7-yl)nitrile et application a la synthese de l'ivabradine
FR2940287B1 (fr) * 2008-12-24 2010-12-24 Servier Lab Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable.
FR2941695B1 (fr) * 2009-02-04 2011-02-18 Servier Lab Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable

Also Published As

Publication number Publication date
MA34276B1 (fr) 2013-06-01
US20130158256A1 (en) 2013-06-20
CY1115682T1 (el) 2017-01-25
CL2012003136A1 (es) 2014-08-01
SI2607353T1 (sl) 2014-12-31
PL2607353T3 (pl) 2015-01-30
MX2012012938A (es) 2013-06-19
GEP20156350B (en) 2015-08-25
CN103172566A (zh) 2013-06-26
WO2013093220A1 (fr) 2013-06-27
TW201326132A (zh) 2013-07-01
ES2525032T3 (es) 2014-12-16
RS53541B1 (en) 2015-02-27
US8513410B2 (en) 2013-08-20
DK2607353T3 (en) 2014-12-08
HRP20141023T1 (hr) 2014-12-05
JO3031B1 (ar) 2016-09-05
SG191471A1 (en) 2013-07-31
KR20130071350A (ko) 2013-06-28
EA201201385A1 (ru) 2013-06-28
MD4336B1 (ro) 2015-03-31
PT2607353E (pt) 2014-10-10
BR102012028614A2 (pt) 2014-12-16
MY170662A (en) 2019-08-26
ZA201208160B (en) 2013-06-26
AU2012244188B2 (en) 2015-07-30
HK1186733A1 (zh) 2014-03-21
NZ603483A (en) 2014-02-28
KR101470879B1 (ko) 2014-12-09
AU2012244188A1 (en) 2013-07-04
UA111329C2 (uk) 2016-04-25
EP2607353A1 (fr) 2013-06-26
PE20131097A1 (es) 2013-10-12
AR088678A1 (es) 2014-06-25
CA2795741C (fr) 2015-09-08
CA2795741A1 (fr) 2013-06-20
EA026510B1 (ru) 2017-04-28
CN103172566B (zh) 2015-11-18
JP5670406B2 (ja) 2015-02-18
FR2984319B1 (fr) 2013-12-27
TWI440627B (zh) 2014-06-11
SA112330994B1 (ar) 2015-08-03
UY34423A (es) 2013-07-31
FR2984319A1 (fr) 2013-06-21
JP2013129650A (ja) 2013-07-04
MD4336C1 (ro) 2015-10-31

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